Leptospirosis is considered by the Centers for Disease Control to be the most widespread zoonosis in the world. Reservoir hosts with chronic renal tubular infection typically transmit pathogenic Leptospira species to humans through urinary shedding. Leptospiral infection in humans frequently results in fulminate liver dysfunction, kidney failure, and severe pulmonary hemorrhage syndrome with a mortality rate of >10%. Leptospirosis has emerged as a major public health burden in urban slums where risk is strongly linked to poverty and rat exposure. L. interrogans serovar Copenhageni is the most common organism isolated from the urban brown rat (Rattus norvegicus) is also the predominant cause of human leptospirosis in urban slums. There is a need to develop oral vaccination strategies to prevent renal carriage in the reservoir host and the risk of leptospirosi in at-risk human populations. The overall goal of this proposal is to understand the role(s) of surface-exposed outer membrane proteins (OMPs) in the mechanisms of leptospiral pathogenesis and immunity. We hypothesize those OMPs that are unregulated as pathogenic leptospires transition from the environment into the mammalian host tissues are key targets for a protective immune response. In support of this hypothesis, we have found that the leptospiral immunoglobulin-like (Lig) proteins are dramatically unregulated by temperature and osmolarity, play multiple roles in host- pathogen interactions, and have been shown to be effective protective immunogens. We propose the following interrelated but not interdependent Aims: 1) Examine the transcriptional and post-transcriptional mechanisms that regulate Lig expression; 2) Determine which surface-exposed OMPs are involved in mechanisms of leptospiral pathogenesis & immunity; 3) Determine which leptospiral OMPs are most effective at inducing sterilizing immunity. In pursuit of these aims, we will examine the molecular mechanisms by which OMPs are regulated, identify additional OMP adhesions and examine their roles in pathogenesis and immunity, and develop E. coli and Lactobacillus oral OMP-based vaccines that prevent acquisition of renal infection by reservoir hosts and effectively block shedding of pathogenic leptospires. This information is critical to understanding how to reduce environmental contamination with and preventing exposure to these potentially life-threatening bacterial pathogens.